Oncotarget

Research Papers:

Ral A, via activating the mitotic checkpoint, sensitizes cells lacking a functional Nf1 to apoptosis in the absence of protein kinase C

Suthakar Ganapathy, Johan B Fagman, Ling Shen, Tianqi Yu, Xiaodong Zhou, Wei Dai, Alexandros Makriyannis and Changyan Chen _

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Oncotarget. 2016; 7:84326-84337. https://doi.org/10.18632/oncotarget.12607

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Abstract

Suthakar Ganapathy1,*, Johan B Fagman2,*, Ling Shen1, Tianqi Yu1, Xiaodong Zhou1,3, Wei Dai4, Alexandros Makriyannis1, Changyan Chen1

1Center for Drug Discovery, Northeastern University, Boston, MA, USA

2The Institute of Clinic Sciences, Sahlgrenska Academy, Gothenburg, SE

3The First Affiliated Hospital of Nanchang University, Nanchang, China

4Department of Environmental Medicine, New York University, Tuxedo, NY, USA

*These authors contributed equally to this work

Correspondence to:

Changyan Chen, email: c.changyan@neu.edu

Keywords: Nf1, Ral A, Chk1, mitotic catastrophe, apoptosis

Received: August 01, 2016     Accepted: October 04, 2016     Published: October 12, 2016

ABSTRACT

Nf1 mutations or deletions are suggested to underlie the tumor predisposition of NF1 (neurofibromatosis type 1) and few treatments are available for treating NF1 patients with advanced malignant tumors. Aberrant activation of Ras in Nf1-deficient conditions is responsible for the promotion of tumorigenesis in NF1. PKC is proven to be an important factor in supporting the viability of Nf1-defected cells, but the molecular mechanisms are not fully understood. In this study, we demonstrate that the inhibition of protein kinase C (PKC) by 1-O-Hexadecyl-2-O-methyl-rac-glycerol (HMG, a PKC inhibitor) preferentially sensitizes Nf1-defected cells to apoptosis, via triggering a persistent mitotic arrest. In this process, Ral A is activated. Subsequently, Chk1 is phosphorylated and translocated to the nucleus. Silencing Ral A significantly blocks Chk1 nuclear translocation and releases HMG-treated Nf1-deficient cells from mitotic arrest, resulting in the reduction of the magnitude of apoptosis. Thus, our study reveals that PKC is able to maintain the homeostasis or viability of Nf1-defected cells and may serve as a potential target for developing new therapeutic strategies.


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